Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

ABSTRACT

Hydroxy-substituted azetidinone hypocholesterolemic agents of the formulaor a pharmaceutically acceptable salt thereof, wherein:Ar1 and Ar2 are aryl or R4-substituted aryl;Ar3 is aryl or R5-substituted aryl;X, Y and Z are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-;R and R2 are -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7;R1 and R3 are H or lower alkyl;q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5;R4 is selected from lower alkyl, R5, -CF3, -CN, -NO2 and halogen R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6;R6, R7 and R8 are H, lower alkyl or aryl-substituted IcR9 is lower alkyl, aryl or aryl-substituted lower alkyl;are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them.

The present application is the United States national applicationcorresponding to International Application No. PCT/US94/10099, filedSep. 14, 1994 and designating the United States, which PCT applicationis in turn a continuation-in-part of U.S. application Ser. No.08/257593, filed Jun. 9, 1994, U.S. Pat. No. 5,631,365, which is acontinuation-in-part of U.S. application Ser. No. 08/102,440, filed Sep.21, 1993, abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to hydroxy-substituted azetidinones usefulas hypocholesterolemic agents in the treatment prevention ofatherosclerosis, and to the combination of a hydroxy-substitutedazetidinone of this invention and a cholesterol bioxynthesis inhibitorfor the treatment and prevention of atherosclerosis. The invention alsorelates to a process for preparing hydroxy-substituted azetidinones.

Atherosclerotic coronary heart disease (CHD) represents the major causefor death and cardiovascular morbidity in the western world. Riskfactors for atherosclerotic coronary heart disease include hypertension,diabetes mellitus, family history, male gender, cigar smoke and serumcholesterol. A total cholesterol level in excess of 225-250 mg/dl isassociated with significant elevation of risk of CHD.

Cholesteryl esters are a major component of atherosclerotic lesions andthe major storage form of cholesterol in arterial wall cells. Formationof cholesteryl esters is also a key step in the intestinal absorption ofdietary cholesterol. Thus, inhibition of cholesteryl ester formation andreduction of serum cholesterol is likely to inhibit the progression ofatherosclerotic lesion formation, decrease the accumulation ofcholesteryl esters in the arterial wall, and block the intestinalabsorption of dietary cholesterol.

A few azetidinones have been reported as being useful loweringcholesterol and/or in inhibiting the formation of cholesterol-containinglesions in mammalian arterial walls. U.S. Pat. No. 4,983,597 disclosesN-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram, et al.,in Indian J. Chem., Sect. B. 29B, 12 (1990), p. 1134-7, disclose ethyl4-(2-oxoazetidin-4-yl)phenoxy-alkanoates as hypolipidemic agents.European Patent Publication 264,231 discloses1-substituted-4-phenyl-3-(2-oxo-alkylidene)-2-azetidinones as bloodplatelet aggregation inhibitors. European Patent 199,630 and EuropeanPatent Application 337,549 disclose elastase inhibitory substitutedazetidinones said to be useful treating inflammatory conditionsresulting in tissue destruction which are associated with variousdisease states, e.g. atherosclerosis.

WO93/102048, published Feb. 4, 1993, discloses substituted β-lactamsuseful as hypocholesterolemic agents.

The regulation of whole-body cholesterol homeostasis in humans andanimals involves the regulation of dietary cholesterol and modulation ofcholesterol biosynthesis, bile acid biosynthesis and the catabolism ofthe cholesterol-containing plasma lipoproteinis. The liver is the majororgan responsible for cholesterol biosynthesis and catabolism and forthis reason, it is a prime determinant of plasma cholesterol levels. Theliver is the site of synthesis and secretion of very low densitylipoproteins (VLDL) which are subsequently metabolized to low densitylipoproteins (LDL) in the circulation. LDL are the predominantcholesterol-carrying lipoproteins in the plasma and an increase in theirconcentration is correlated with increased atherosclerosis.

When intestinal cholesterol absorption is reduced, by whatever means,less cholesterol is delivered to the liver. The consequence of thisaction is decreased hepatic lipoprotein (VLDL), production and anincrease in the hepatic clearance of plasma cholesterol, mostly as LDL.Thus, the net effect of inhibiting intestinal cholesterol absorption isa decrease in plasma cholesterol levels.

The inhibition of cholesterol biosynthesis by 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown tobe an effective way to reduce plasma cholesterol (Witzum, Circulation,80, 5 (1989), p. 1101-1114) and reduce atherosclerosis. Combinationtherapy of an HMG CoA reductase inhibitor and a bile acid sequestranthas been demonstrated to be more effective in human hyperlipidemicpatients than either agent in monotherapy (Illingworth, Drugs, 36(Suppl. 3) (1988), p. 63-71).

SUMMARY OF THE INVENTION

Novel hypocholesterolemic compounds of the present invention arerepresented by the formula I

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ and Ar² are independently selected from the group consisting of aryland R⁴-substituted aryl;

Ar³ is aryl or R⁵-substituted aryl;

X, Y and Z are independently selected from the group consisting of—CH₂—, —CH(lower alkyl)— and —C(dilower alkyl)—;

R and R² are independently selected from the group consisting of —OR⁶,—O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷;

R¹ and R³ are independently selected from the group consisting ofhydrogen, lower alkyl and aryl;

q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4;provided that at least one of q and r is 1, and the sum of m, n, p, qare r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1,the sum of m, q and n is 1, 2, 3, 4, or 5;

R⁴is 1-5 substituents independently selected from the group consistingof lower alkyl, —OR⁶, —O(CO)R₆, R⁶ , —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶,—O(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO) NR⁷R⁸, —NR⁶SO₂R⁹,—COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶,—O(CH₂)₁₋₁₀CONR⁶R⁷, —(lower alkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN,—NO₂ and halogen;

R⁵ is 1-5 substituents independently selected from the group consistingof —OR⁶, —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷, —NR⁶R⁷,—NR⁶(CO) R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷,—COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷,—(lower alkylene)COOR⁶ and —CH═CH—COOR⁶;

R⁶, R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and

R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.

R⁴ is preferably 1-3 independently selected substituents, and R⁵ ispreferably 1-3 independently selected substituents. Preferred arecompounds of formula I wherein Ar¹ is phenyl or R⁴-substituted phenyl,especially (4-R⁴)-substituted phenyl, Ar² is preferably phenyl orR⁴-substituted phenyl, especially (4-R⁴)-substituted phenyl. Ar³ ispreferably R⁵-substituted phenyl, especially (4-R⁵)-substituted phenyl.When Ar¹ is (4-R⁴)-substituted phenyl, R⁴ is preferably a halogen. WhenAr² and Ar³ are R⁴- and R⁵-substituted phenyl, respectively, R⁴ ispreferably halogen or —OR⁶ and R⁵ is preferably —OR⁶, wherein R₆ islower alkyl or hydrogen. Especially preferred are compounds wherein eachof Ar¹ and Ar² is 4-fluorophenyl and Ar³ is 4-hydroxyphenyl or4-methoxyphenyl.

X, Y and Z are each preferably —CH₂—.R¹ and R³ are each preferablyhydrogen. R and R² are preferably —OR⁶ wherein R⁶ is hydrogen, or agroup readily metabolizable to a hydroxyl (such as —O(CO)R⁶, —O(CO)OR⁹and —OR⁶, especially —O(CO)NR⁶R⁷, defined above).

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.Preferred are compounds wherein m, n and r are each zero, q is 1 and pis 2. Also preferred are compounds wherein p, q and n are each zero, ris 1 and m is 2 or 3. More preferred are compounds wherein m, n and rare each zero, q is 1, p is 2, Z is —CH₂ and R is —OR⁶OR₆, especiallywhen R⁶ is hydrogen. Also more preferred are compounds wherein p, q andn are each zero, r is 1, m is 2, X is —CH₂— and R² is —OR⁶, especiallywhen R⁶ is hydrogen.

Another group of preferred compounds is that wherein Ar¹ is phenyl orR⁴-substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl and Ar³ isR⁵-substituted phenyl. Also preferred are compounds wherein Ar¹ isphenyl or R⁴-substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl,Ar³ is R⁵-substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or4, more especially 3. More preferred are compounds wherein Ar¹ is phenylor R⁴-substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl Ar³ isR⁵-substituted phenyl, and wherein m, n and r are each zero, q is 1 andp is 2, or wherein p, q and n are each zero, r is 1 and m is 2 or 3.

This invention also relates to a method of lowering the serumcholesterol level in a mammal in need of such treatment comprisingadministering an effective amount of a compound of formula I. That is,the use of a compound of the present invention as an hypocholesterolemicagent is also claimed.

In still another aspect, the present invention relates to apharmaceutical composition comprising a serum cholesterol-loweringeffective amount of a compound of formula I in a pharmaceuticallyacceptable carrier.

The present invention also relates to a method of reducing plasmacholesterol levels, and to a method of treating or preventingatherosclerosis, comprising administering to a mammal in need of suchtreatment an effective amount of a combination of a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I and acholesterol biosynthesis inhibitor. That is, the present inventionrelates to the use of a hydroxy-substituted azetidinone cholesterolabsorption inhibitor of formula I for combined use with a cholesterolbiosynthesis inhibitor (and, similarly, use of a cholesterolbiosynthesis inhibitor for combined use with a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I) to treat orprevent atherosclerosis or to reduce plasma cholesterol levels.

In yet another aspect, the invention relates to a pharmaceuticalcomposition comprising an effective amount of a hydroxy-substitutedazetidinone cholesterol absorption inhibitor of formula I, a cholesterolbiosynthesis inhibitor, and a pharmaceutically acceptable carrier. In afinal aspect, the invention relates to a kit comprising in one containeran effective amount of a hydroxy-substituted azetidinone cholesterolabsorption inhibitor of formula I in a pharmaceutically acceptablecarrier, and in a separate container, an effective amount of acholesterol biosynthesis inhibitor in a pharmaceutically acceptablecarrier.

In yet another aspect, the invention relates to a process for preparingcertain compounds of formula I comprising the steps:

(a) treating with a strong base a lactone of the formula

wherein R′ and R²′ are R and R², respectively, or are suitably protectedhydroxy groups; Ar¹⁰ is Ar¹, a suitably protected hydroxy substitutedaryl or a suitably protected amino-substituted aryl; and the remainingvariables are as defined above, provided that in lactone of formula Bwhen n and r are each zero, p is 1-4;

(b) reacting the product of step (a) with an imine of the formula

wherein Ar²⁰ is Ar², a suitably protected hydroxy-substituted aryl or asuitably protected amino-substituted aryl; and Ar³⁰ is Ar³, a suitablyprotected hydroxy-substituted aryl or a suitably protectedamino-substituted aryl;

c) quenching the reaction with an acid;

d) optionally removing the protecting groups from R′, R^(2′), Ar¹⁰, Ar²⁰and Ar³⁰, when present; and

e) optionally functionalizing hydroxy or amino substituents at R, R²,Ar¹, Ar² and Ar³.

Using the lactones shown above, compounds of formula IA and IB areobtained as follows:

wherein the variables are as defined above; and

wherein the variables are as defined above.

DETAILED DESCRIPTION

As used herein, the term “lower alkyl” means straight or branched alkylchains of 1 to 6 carbon atoms.

“Aryl” means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.

“Halogen” refers to fluorine, chlorine, bromine or iodine atoms.

The above statement, wherein R⁶, R⁷ and R⁸ are said to be independentlyselected from a group of substituents, means that R⁶, R⁷ and R⁸ areindependently selected, but also that where an R₆ , R⁶ or R⁸ variableoccurs more than once in a molecule, those occurrences are independentlyselected (e.g., if R is —OR⁶ wherein R⁶ is hydrogen, R⁴ can be —OR⁶wherein R⁶ is lower alkyl).

Compounds of the invention have at least one asymmetric carbon atom andtherefore all isomers, including enantiomers and diastereomers arecontemplated as being part of this invention. The invention includes dand I l isomers in both pure form and in admixture including racemicmixtures. Isomers can be prepared using conventional techniques, eitherby reacting chiral starting materials or by separating isomers of acompound of formula I. Isomers may also include geometric isomers, e.g.when a double bond is present. All such geometric isomers arecontemplated for this invention.

Those skilled in the art will appreciate that for some compounds offormula I, one isomer will show greater pharmacological activity thananother isomer.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase form for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Cholesterol biosynthesis inhibitors for use in the combination of thepresent invention include HMG CoA reductase inhibitors such aslovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoAsynthetase inhibitors, for example L-659,699((E,E)-11-[3′-R-(hydroxy-methyl)-4′-oxo-2′-R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other cholesterol biosynthesis inhibitors such asDMP-565. Preferred HMG CoA reductase inhibitors are lovastatin,pravastatin and simvastatin.

Compounds of formula I can be prepared by known methods, for examplethose described below and in WO93/02048.

Compounds of formula Ia and Ib, wherein Ar¹, Ar², Ar3, Ar ³ X, Y, Z, R¹,R², R³, m, n, p, q and r are as defined above, can be prepared bytreatment of an ester of formula III, wherein R¹⁰ is lower alkyl such asethyl or a chiral moiety such as menthyl or10-(diisopropylsulfonamido)isobornyl, and the remaining variables are asdefined above, with a strong base such as lithium diisopropylamide (LDA)in a suitable solvent such as tetrrahydrolithium (THF) at −78° C. Asolubilizing agent such as hexamethylphosphoric triamide (HMPA) mayoptionally be added as a cosolvent. An imine of formula 11, wherein Ar²⁰and Ar³⁰ are as defined above, is added, the reaction mixture is eitherwarmed to room temperature or maintained at a suitable low temperaturesuch as −78° C. for the appropriate time, followed by quenching with asuitable acid such as 1N HCl. The product is isolated using conventionalpurification techniques. When a protecting group as defined in Table 1(below) is present on one or more of the optionally protected groups, anadditional step comprising removal of the protecting group byconventional techniques is needed. However, for compounds of formula Ia,Ib, or any compound of formula I wherein a protected hydroxy group Ar¹⁰,Ar²⁰, Ar³⁰, R′ or R²′ is an alkoxy or benzyloxy group, such a protectinggroup need not be removed to obtain a compound of formula I. When achiral ester of formula III is used, the resulting compound of formulaIa or Ib is not racemic.

Imines of formula II (Ar³⁰—CH═N—Ar²⁰) can be prepared from aldehydes ofthe formula Ar³⁰—CHO and amines of the formula Ar⁺—CHO and Ar²⁰ —NH ₂ byprocedures well known in the art. Aldehydes of formula Ar⁺Ar³⁰—CHO andamines of formula Ar²⁰—NH₂ are commercially available or can be preparedvia known procedures.

Compounds of formula Ic and Id, wherein the variables are as definedabove, can be prepared by a process comprising the following steps:

(a) Treat a lactone of formula IV, wherein the variables are as definedabove, with a strong base such as an alkyllithium (e.g.,n-butyl-lithium), a metal hydride (e.g., sodium hydride), a metalalkoxide (e.g., sodium methoxide), a metal halide (e.g., TiCl₄), metalexchange of the lithium enolate with a metal halide (e.g., zincchloride), metal exchange of the lithium enolate with a metal alkyl(e.g., 9-borabicyclononyl triflate), or, preferably, a metalamide (e.g.,LDA), in a suitable anhydrous organic solvent such as dry THF, ether orbenzene, in a dry, inert atmosphere, e.g., under nitrogen. The reactionis carried out at about 0° C. to about −85° C., preferably about −78°C., over a period of about 5 to about 60 minutes, preferably about 30minutes. 1-50% of solubilizing cosolvents may optionally be added,preferably about 10% HMPA.

(b) Add an imine of formula 11, wherein Ar²⁰ and Ar³⁰ are as definedabove, to the product of step (a) over a period of 5 to 60 minutes,preferably 30 minutes, maintaining the reaction mixture at about 0° C.to about −85° C., preferably about −78° C., for 1 to 12 hours,preferably about 3 hours, or warming the reaction mixture over that timeperiod at a rate of about 10° C. per hour to about 70° C. per hour,preferably about 30° C. per hour, to a temperature of about 20° C.

(c) Quench the reaction with a suitable acid such as HCl (1N).

(d) The protecting groups on R′, R²′, Ar¹⁰, Ar²⁰ and Ar³⁰, when present,are removed, if desired, by methods well known in the art, for examplesilyl protecting groups are removed by treatment with fluoride.

e) Compounds of formula I wherein any of R and R², when present, are OR⁶wherein R⁶ is hydrogen, can be converted by well known methods to othercompounds of formula I wherein R and R² are functionalized, i.e., areindependently selected from the group consisting of OR^(6a), —O(CO)R⁶,—O(CO)OR⁹ and —O(CO)NR⁶R⁷, wherein R⁶, R⁷ and R⁹ are as defined aboveand R^(6a) is lower alkyl, aryl, or aryl-lower alkyl. For example,treatment of the alcohol with an alkyl halide in the presence of asuitable base such as NaH will afford alkoxy-substituted compounds(i.e., R or R² is OR⁶, wherein R⁶ is lower alkyl); treatment of thealcohol with an acylating agent such as acetylchloride will result incompounds wherein R or R² is —OC(O)R⁶; treatment of the alcohol withphosgene followed by an alcohol of the formula HOR⁹ affords compoundssubstituted with a —OC (O)OR⁹ group; and treatment of the alcohol withphosgene followed by an amine of the formula HNR⁶R⁷ affords compoundswherein R or R² is —OC(O)NR⁶R⁷. Compounds of formula I wherein any Ar¹,Ar² or Ar³ has a hydroxy or amino group can be similarly functionalizedto obtain other compounds of formula 1, i.e., wherein R⁴ and R⁵ areindependently —OR^(6a), —O(CO)R⁶, —O(CO)OR⁹, —O(CH₂)₁₋₅OR⁶, —O(CO)NR⁶R⁷,—NR⁶R⁷, —NR⁶(CO) R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸ or —NR⁶SO₂R⁹.

The product of step c, d or e is isolated using conventionalpurification techniques such as extraction, crystallization or,preferably, silica gel 60 chromatography. When a chiral lactone is used,the resulting compound of formula Ic or Id is not racemic.

Using the procedure described in steps (a)-(e), lactones of formula IVacan be used to prepare compounds of formula Ig and Ih, provided thatwhen n and r are each zero, p is 1-4:

Lactones of formulae IV and IVa are known in the art or can be preparedby methods well known in the art. See, for example, U.S. Pat. No.4,375,475 and J. Agric. Food Chem., 30 (5) (1982) p. 920-4.

Azetidinones of formula V, wherein Ar²⁰ and Ar³⁰ are as defined above,can be reacted to form compounds of formula Ie and If i.e., compounds offormula I wherein r is 1, R² is hydroxy, and p is zero) by treatment ofazetidinone V with a strong base such as lithiumiosoproptylcyclohexylamide isopropylcyclohexylamide in a suitablesolvent such as THF in the presence or absent absence of HMPA at −78°C., followed by the addition of an aldehyde or ketone of VI, whereinAr¹⁰, X, Y, R′, R¹, R³, m, n and q are as defined above. As in the caseof Method A, protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R′ and R^(2′) areremoved as necessary.

This process provides several of the possible diastereomers which can beseparated by a combination of crystallization, silica gel chromatographyand HPLC, using techniques well known in the art. The remainingdiastereomers can be obtained by inversion reactions such as theMitsunobu reaction sequence outlined below, wherein partial structuresof formula If are shown:

In the above known process, DEAD is diethylazodicarboxylate and PPh₃ istriphenylphosphine. The reactants are stirred at room temperatureovernight and the resultant formate ester is converted to thecorresponding hydroxy compound with the desired stereochemistry.

Compounds of formula Ia as defined above can be prepared by reacting achiral auxiliary such as the compound of formula VIII with an activatedcarboxylic acid derivative of formula VII, for example an acid chloride(L═Cl), a mixed anhydride formed with phenyl phosphorodichloridate(L═OP(O)(Cl)OPh), an N-methyl-pyridinium ester formed from the reactionof an acid with N-methyl-2-chloropyridinium iodide(L=2-oxy-N-methylpyridinium iodide), and a 2-thiopyridyl ester formedfrom the reaction of an acid chloride and 2-thiopyridine, wherein theremaining variables are as defined above; enolizing the resultantproduct, for example with TiCl₄ and tetramethylethylenediamine (TMEDA);condensing with an aldehyde, Ar³⁰CHO; hydrolyzing to the correspondingacid, then reacting the compound of formula IX with an amine, Ar²⁰NH₂;and cyclizing the resultant compound of formula X, with, for example atrialkylphosphine and a dialkylazodicarbo)ylate. As in the case ofMethod A, protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R′ and R^(2′) areremoved as necessary. This procedure is described in detail inWO93/102048 WO93/02048.

Compounds of formula Ia as defined above can also be prepared treatmentof an imine of formula 11, II, wherein Ar²⁰ and Ar³⁰ are as definedabove, with an activated carboxylic acid derivative of formula VII asdefined above in the presence of a tertiary amine base such astriethylamine, tributylamine or diethylisopropylamine in an inertsolvent such as CH₂Cl₂. Again, as in the case of Method A, protectinggroups at Ar¹⁰, Ar²⁰, Ar³⁰, R′ and R²′ are removed as necessary. Use ofother bases, e.g., pyridine, favors formation of compounds of formulaIb.

In the first step, compound XII is dissolved in a suitable solvent,e.g., anhydrous CH₂Cl₂, and treated with a Lewis acid, e.g., TiCl₄ atabout −60° C. to 0° C., preferably at about −25° C., under a dry, inertatmosphere, e.g., argon. A tertiary amine base such as TMEDA is addedand the mixture stirred at about −60° C. to 0° C., preferably at about−25° C. to −15° C., for a period of about 1 h. An imine of formulaAr³⁰CH═NAr²⁰ is added neat or optionally as a solution in a suitablesolvent, e.g. anhydrous CH₂Cl₂, over a period of about 5 min, and thereaction is stirred vigorously at about −60° C. to 0° C., preferably atabout −25° C. to −15° C., for about 3 to 6 h, preferably about 4 h oruntil the reaction is complete by TLC. An acid, e.g. acetic acid, isadded to reaction at the reaction temperature and the mixture is allowedto warm to room temperature slowly with stirring for about 1-3 hours,preferably about 2 hours. The compound of formula XII is isolated byextraction with a suitable solvent, e.g. CH₂Cl₂, then purified bycrystallization or silica gel chromatography.

In the second step, the product is treated with a strongnon-nucleophilic base, such as sodium or lithium bistrimethylsilylamideat about −78° C. to 100° C. After reaction, the mixture is poured intoaqueous tartaric acid and the product isolated from the organic layer.As in the case of Method A, protecting groups at Ar¹⁰, Ar²⁰, Ar³⁰, R′and R^(2′) are removed as necessary. This process, including thepreparation of the starting material of formula XII, is also describedin greater detail in WO93/02048.

Compound of formula Ig′ and Ih′ (i.e., compounds of formula I wherein Ris OH), wherein R²′ is a protected hydroxy group as defined above, andthe remaining variables are as defined above, can be prepared byreacting an imine of formula 11II and a carboxylic acid derivative offormula XIV, wherein the variables are as defined above, according toMethod D, followed by oxidation of the resultant halide of formula XV bytreatment with an oxidizing agent such as trimethylamine oxide, CrO₃ orozone in a solvent such as DMSO. The resultant aldehyde or ketone offormula XVI is then reacted with an aryl organometallic reagent (e.g.,Ar¹⁰X_(m)MgBr, Ar¹⁰X_(m)Li, Ar¹⁰X_(m)MgCl or Ar¹⁰X_(m)CeCl₂) to obtain acompound of formula Ig′ or Ih′. As described above, the Ar¹⁰, Ar²⁰, Ar³⁰and R^(2′) substituents can be converted to the desired Ar¹, Ar², Ar³and R² substituents by procedures well known in the art.

Compounds of formula Ii having a hydroxy substituent on the side chainadjacent to the Ar¹ group (i.e., compounds of formula I wherein m is 0)can be prepared by heating a compound of formula XVII, prepared byMethod D, above, wherein the variables are as defined above, for about1-6 hours at about 60° C. to 100° C. with a halogenating agent such asN-bromosuccinimide (NBS) in a suitable solvent such as CCl₄ in thepresence of an initiating agent such as benzoyl peroxide. The resultantcompound of formula XVIII, wherein Hal is Cl, Br or I and the remainingvariables are as defined above, is then heated in a suitable solventsuch as CH₂Cl₂ with a tetraalkyl-ammonium salt such as tetran-butyl-ammonium hydroxide (n-Bu₄NOH) to obtain the compound of formulaIa. Alternatively, compound XVIII can be heated in a suitable solventsuch as CH₂Cl₂ with tetra n-butylammonium trifluoroacetate(n-Bu₄NOC(O)CF₃) followed by treatment with a mild base such as ethanolsaturated with NH3 NH ₃ to obtain compound Ii,

Compounds of formula Ij (i.e., compounds of formula I wherein R is OH,R¹ is H and q is 1) are prepared from compound XIX in 2 steps. First, acompound of formula XIX, wherein the variables are as defined above, isdissolved in a suitable anhydrous solvent, e.g. THF, at about −20° C. toabout 22° C., preferably at about 0° C. under a dry inert atmosphere,e.g. argon and adding a transition metal source, e.g.tetrakis(triphenylphosphine)-palladium or palladium acetate/triphenylphosphine. An organometallic of formula Ar¹⁰-Xm _(m)-Met, wherein inAr¹⁰, X and m are as defined above and Met is, for example, ZnCl orB(OH)₂, is added to the reaction mixture at about −20° C. to about 22°C., preferably at about 0° C., the reaction mixture is stirred for about15 min to 4 h, preferably about 1 h, and is then allowed to warm toabout 22° C. Addition of dilute acid, e.g. 1N HCl, followed byextraction with a suitable organic solvent, e.g. ethyl acetate (EtOAc),produces compound XX.

The ketone of-formula XX is dissolved in a suitable solvent e.g. CH₃OH,a hydrogenation catalyst is added, e.g. Pd on carbon, and the mixture isexposed to H₂ gas under a pressure of about 14 psi to 100 psi,preferably about 60 psi for about 1 to 24 h, preferably, about 16 h. Thehydrogenation catalyst is removed by filtration and the solvent isremoved in vacuo to produce a compound Ij as a mixture of alcoholdiastereomers which can be separated by conventional means.

Alternatively, a ketone of formula XX is dissolved in a suitablesolvent, e.g. THF, at about −40° C. to about 22° C., preferably at about0° C., and a suitable reducing agent such as NaBH₄, a substitutedborohydride (e.g., [cbz-proline] ₃BHNa) or a borane is adlded,optionally in the presence of a suitable chiral promotor present eitherin catalytic or stoichiometric amounts, e.g., chiral borane ofstructures:

Addition of dilute acid, e.g., 1N HCl, followed by extraction with asuitable solvent produces compounds of formula Ij. As above, protectinggroups at Ar¹⁰, Ar²⁰, Ar³⁰ and R²′ are removed as necessary. When eithera chiral reagent or a chiral promotor is used, the resulting product isnon-racemic.

Compounds of formula XIX can be prepared by a multi-step procedure asrepresented below:

Compounds of formula XXI, wherein R¹⁰ is lower alkyl and the remainingvariables are as defined above, are commercially available or can beprepared by treating the corresponding carboxylic acid (i.e., compoundswherein the Cl is replaced by a hydroxy group) with a chlorinatingagent, e.g. SOCl ₂ or oxalyl chloride, under a dry atmosphere, neat orin a suitable inert organic solvent, e.g. toluene at about 40° C. to110° C., preferably about 70° C.; alternatively, a catalyst made beadded, e.g. dimethylformamide (DMF), the reaction is conducted at about22° C., and the solvent and excess reagents are removed in vacuo. Thecompound XXI is reacted with a chiral auxiliary such as (S)- 4 -phenyl-2 -oxazolidinone according to the following procedure; a chiralauxiliary is treated with a strong base such as an alkyllithium, a metalhydride or a tertiary amine base such as triethylamine, in a suitableanhydrous organic solvent, e.g., dry THF, under a dry, inert atmosphere,e.g. argon at about −85° C., to 22° C., preferably about 0° C., forabout 10 min to 60 min, preferably about 30 minutes. The resulting anionis reacted, without isolation, with compound XXI in a suitable anhydrousorganic solvent, e.g. dry THF, under a dry, inert atmosphere, e.g. argonat about −85° C. to about 22° C., preferably 0° C., for about 30 min to60 min, preferably 30 min. The reaction is warmed to about 22° C. andcontinued for 1 to 12 h, preferably 6 h. Water is added and compoundXXII is isolated by extraction and purified by crystallization.

The compound of formula XXII is treated in the same manner as describedin step 1 of Method E to obtain a compound XXIII.

Azetidinone ring closure can be accomplished by alternative procedures.By one method, a compound of formula XXIII is treated with a strongnon-nucleophilic base, such as sodium or lithium-bistrimethylsilylamide,in a suitable inert organic solvent, e.g. CH₂Cl₂, at about −78° C. toabout 10° C., preferably about 0° C. The mixture is stirred for about 1to 2 hours while gradually warming to about 22° C. Compound XXIV isisolated by conventional extraction with CH₂Cl₂. In another, two-stepmethod, a compound of formula XXIII is first treated with mildsilylating agent, e.g. N,O-bis(trimethylsilyl)acetamide at about 0° C.to about 100° C., preferably about 40° C. for about 10 min to 60 min,preferably 30 min, then treated with a fluoride anion source, e.g.tetrabutylammonium fluoride (TBAF), at about 0° C. to about 100° C.,preferably 40° C., and allowed to stir for about 0.5 to about 4 hours,preferably about 2 hours. Compound XXIV is isolated by conventionalextraction methods.

The compound of formula XXIV is hydrolysed by a suitable base, e.g.LiOH, in a suitable solvent, e.g. 66% CH₃OH/water at about 0° C. toabout 50° C., preferably 22° C., for about 1 to 4 hours, preferably 2hours, then extracted with a suitable solvent, e.g. EtOAc. The resultingacid is converted to the acid chloride as described above by treatmentwith a chlorination agent, e.g. oxalyl chloride, to afford compound

Compounds of formula Ik, wherein Ar¹, Ar², Ar³ and R¹ are as definedabove, one of X″ and Y″ is —CH₂CH₂— and the other is selected from thegroup consisting of —CH₂CH₂—, —CH₂—, —CH(lower alkyl)-, —CH (diloweralkyl) and a bond, are prepared by oxidation of an alkene of formulaXXV, wherein one of X′ and Y′ is —CH═CH— and the other is —CH═CH—,—CH₂—, —CH₂CH₂—, —CH(lower alkyl)-, —CH(dilower alkyl) or a bond, andthe remaining variables are as defined above, can be prepared by thefollowing two step procedure.

A compound of formula XXV, which can be prepared by Method D, above, istreated with an oxidizing agent such as SeO₂, phenylselenic anhydride orCrO₃ in a suitable solvent such as dioxane at about 22° to 100° C. forabout 0.5 to 12 hours. After the starting material is consumed asdetermined by TLC, or 12 hours, the reaction is cooled to about 22° C.and the product XXVI is isolated by extraction.

In the second step, an allylic alcohol of formula XXVI is dissolved in asuitable solvent, e.g., EtOAc, a hydrogenation catalyst added, e.g., Pdon carbon, and the mixture is exposed to H₂ gas under a pressure ofabout 14 psi to 60 psi for about 1 to 12 hours. The hydrogenationcatalyst is removed in vacuo to obtain a compound of formula Ik.

Alcohols of formula Im and In (i.e., compounds of formula I where r is1, R² is —OH, R³ is hydrogen and p is 0) can be selectively obtainedfrom ketones of formula XXVII in three steps comprising bromination,reduction and debromination. Since the stereochemistry of the majorisomers of alcohols XXIXa and XXIXb are different, one can selectivelyprepare either diastereomeric alcohol.

In the above process, a ketone of formula XXVII, which can be preparedby oxidation of the corresponding hydroxy compound by well knownmethods, is halogenated, for example by treatment in an inert solvent,e.g., THF, with NaH followed by N-bromosuccinimide, to obtain a mixtureof 3-bromo-ketone compounds XXVIII (a and b). Compounds 15 XXVIIIa andXXVIIIb are then separately reduced to the corresponding alcohols, forexample by treatment with magnesium trifluoroacetate (Mg(TFA)₂) andt-butylamine borane (t-Bu—NH₂—BH₃) in an inert solvent such as THF at atemperature of about −78° C. to 0° C. The resultant alcohols XXIX aredehalogenated by treatment with tris(trimethylsilyl)silane ((TMS)₃SiH)in a solvent such as toluene in the presence of a radical initiator suchas 2,2′-azobisisobutyronitrile (AIBN) to obtain a mixture of isomers Imand In which can be separated into individual enantiomers byconventional means, e.g., HPLC. Again, protecting groups at Ar¹⁰, Ar²⁰,Ar³⁰ and R′ are removed as necessary.

Starting compounds III, V, VI, VII, VIII, XIV, XVII, XXI and XXV are alleither commercially available or well known in the art and can beprepared via known methods.

Reactive groups not involved in the above processes can be protectedduring the reactions with conventional protecting groups which can beremoved by standard procedures after the reaction. The following Table 1shows some typical protecting groups:

TABLE 1 Group to be Group to be Protected and Protected Protecting Group—COOH —COOalkyl, —COObenzyl, —COOphenyl

—NH₂

—OH

—OSi(CH₃)₃, or —OCH₂phenyl

We have found that the compounds of this invention lower serum lipidlevels, in particular serum cholesterol levels. Compounds of thisinvention have been found to inhibit the intestinal absorption ofcholesterol and to significantly reduce the formation of livercholesteryl esters in animal models. Thus, compounds of this inventionare hypocholesterolemic agents by virtue of their ability to inhibit theintestinal absorption and/or esterification of cholesterol; they are,therefore, useful in the treatment and prevention of atherosclerosis inmammals, in particular in humans.

The in vivo activity of the compounds of formula I can be determined bythe following procedure:

In Vivo Assay of Hypoligidemic Hypolipidemic Agents Using theHyperlipidemic Hamster

Hamsters are separated into groups of six and given a controlledcholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) forseven days. Diet consumption is monitored to determine dietarycholesterol exposure in the face of test compounds. The animals aredosed with the test compound once daily beginning with the initiation ofdiet. Dosing is by oral gavage of 0.2 mL of corn oil alone (controlgroup) or solution (or suspension) of test compound in corn oil. Allanimals moribund or in poor physical condition are euthanized. Afterseven days, the animals are anesthetized by intramuscular (IM) injectionof ketamine and sacrificed by decapitation. Blood is collected intovacutainer tubes containing EDTA for plasma lipid analysis and the liverexcised for tissue lipid analysis. Lipid analysis is conducted as perpublished procedures (Schnitzer-Polokoff, R., et al. Comp. Biochem.Physiol., 99A, 4 (1991), p. 665-670) and data is reported as percentreduction of lipid versus control.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula I and a pharmaceutically acceptablecarrier. The compounds of formula I can be administered in anyconventional dosage form, preferably an oral dosage form such as acapsule, tablet, powder, cachet, suspension or solution. Theformulations and pharmaceutical compositions can be prepared usingconventional pharmaceutically acceptable excipients and additives andconventional techniques. Such pharmaceutically acceptable excipients andadditives include non-toxic compatible fillers, binders, disintegrants,buffers, preservatives, anti-oxidants, lubricants, flavorings,thickeners, coloring agents, emulsifiers and the like.

The daily hypocholesteremic dose of a compound of formula I is about 0.1to about 30 mg/kg of body weight per day, preferably about 0.1 to about15 mg/kg. For an average body weight of 70 kg, the dosage level istherefore from about 5 mg to about 1000 mg of drug per day, given in asingle dose of 2-4 divided doses. The exact dose, however, is determinedby the attending clinician and is dependent on the potency of thecompound administered, the age, weight, condition and response of thepatient.

For the combinations of this invention wherein the hydroxy substitutedazetidinone is administered in combination with a cholesterolbiosynthesis inhibitor, the typical daily dose of the cholesterolbiosynthesis inhibitor is 0.1 to 80 mg/kg of mammalian weight per dayadministered in single or divided dosages, usually once or twice a day;for example, for HMG CoA reductase inhibitors, about 10 to about 40 mgper dose is given 1 to 2 times a day, giving a total daily dose of about10 to 80 mg per day, and for the other cholesterol biosynthesisinhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day,giving a total daily dose of about 1 mg to about 200 mg per day. Theexact dose of any component of the combination to be administered isdetermined by the attending clinician and is dependent on the potency ofthe compound administered, the age, weight, condition and response ofthe patient.

Where the components of a combination are administered separately, thenumber of doses of each component given per day may not necessarily bethe same, e.g. where one component may have a greater duration ofactivity, and will therefore need to be administered less frequently.

Since the present invention relates to the reduction of plasmacholesterol levels by treatment with a combination of active ingredientswherein said active ingredients may be administered separately, theinvention also relates to combining separate pharmaceutical compositionsin kit form. That is, a kit is contemplated wherein two separate unitsare combined: a cholesterol biosynthesis inhibitor pharmaceuticalcomposition and a hydroxy substituted azetidinone cholesterol absorptioninhibitor pharmaceutical composition. The kit will preferably includedirections for the administration of the separate components. The kitform is particularly advantageous when the separate components must beadministered in different dosage forms (e.g. oral and parenteral) or areadministered at different dosage intervals.

Following are examples of preparing compounds of formula I. Thestereochemistry listed is relative stereochemistry unless otherwisenoted. The terms cis and trans refer to the relative orientations at theazetidinone 3- and 4-positions unless otherwise indicated. The term “J”refers to the proton NMR coupling constant in hertz (Hz) between the 3-and 4-substituted protons of the azetidinone. All NMR data is of CDCl₃solution unless otherwise indicated.

Freshly prepare a solution of lithium diisopropylamide (LDA) bydissolving diisopropylamine (1.19 g, 11.8 mmol) in anhydrous THF (20 ml)at −78° C. under argon. Add n-butyllithium (4.9 ml, 11.8 mmol, 2.4M inhexanes) and stir for 0.5 h at −78° C. To this cold solution add,4phenylbutyrolactone (1.75 g, 10.8 mmol) in THF (4 ml) over 0.25 h,keeping the reaction temperature below −65° C. Stir at −78° C. for 0.25h, then add 4-methoxybenzylidine anisidine (2.33 g, 11.0 mmol) in THF (8ml) over 1 h at −78° C. Warm the reaction slowly to −50° C. over 1 h.Quench the reaction at low temperature with 1N HCl (12 ml). Partitionthe reaction mixture between ether and 1N HCl, wash the ether layer withwater, combine the ether extracts, dry over MgSO₄ and concentrate invacuo. Crystallize the crude reaction residue (3.0 g) from EtOAc-etherto obtain 1.54 g of compound A. Reconcentrate the filtrate andchromatograph on silica gel 60, eluting with 4:1 EtOAc-hexane, andisolate additional compound A (0.385 g) as well as compound B (0.420 g).

Compound A: mp 218°-220° C.; IR 1730 cm-1; CI (M−H) 374; J=5.9 Hz.

Compound B: mp 74°-76° C.; IR 1730 cm-1; CI (M+H) 374; J=2.3 Hz.

Using a similar procedure and appropriate starting materials, preparecompound 1C:

Cl(M + H) 464, J = 2.3 Hz

EXAMPLE 2

To a solution of compound A from Example 1 (0.5 g, 1.3 mmol) inanhydrous pyridine (2.7 ml), add acetic anhydride (0.63 ml, 6.7 mmol).Stir for 16 h, dilute with CH₂Cl₂ and wash 3× with 1N HCl 1× with NaCI(sat'd) and 1× with water. Concentrate the organic layer to dryness andcrystallize the residue from EtOAc to obtain the title compound (0.46g), mp 167°-169° C.; IR 1745 cm-1; EI (M+) 415; J=5.9 Hz.

EXAMPLE 3

Freshly prepare a solution of lithium isopropylcyclohexylamide (LICA) byadding n-butyllithium (2.84 mL of a 1.6M solution) to 5 a solution ofisopropylcyclohexylamine (0.75 mL) in THF (100 mL) at −78° C. DissolveN-phenyl-4-(4-methoxyphenyl)-2-azetidinone (1.0 g) in THF (8 mL) andslowly add to the LICA solution at −78° C. After stirring for 20 min,add hydrocinnamaldehyde (0.54 g) and stir the reaction mixture at −78°C. for 4 h. Quench the reaction with 10% KHSO₄ and extract the productwith EtOAc. Separate the organic layer, wash with water and NaCl(sat'd). Concentrate the extract and purify the resultant residue on asilica gel 60 column, eluting with EtOAc:hexane (15:85) to obtain 1.15 gof product as a mixture of diastereomers. Separate the diastereomers byHPLC on a silica gel column to give three diastereomers 3A, 3B and 3C:

3A

1H in CDCl₃:7.32-7.18(m, 11H); 7.08-6.99 (m, 1H); 6.89(d, J = 9 Hz, 2H);4.80(d, J = 2.4 Hz, 1H); 4.10-4.00(m, 1H); 3.79(s, 3H); 3.20-3.16(m,1H); 2.90-2.67(m, 2H); 2.15-1.85(m, 3H) 3B

1H in CDCl₃:7.35-7.10(m, 11H); 7.08-6.99 (m, 1H); 6.89(d, J = 9 Hz, 2H);5.09(d, J = 2.4 Hz, 1H); 4.26-4.14(m, 1H); 3.79(s, 3H); 3.21-3.14(m,1H); 2.89-2.57(m, 2H); 2.10-1.85(m, 3H) 3C

1H in CDCl₃:7.30-7.00(m, 10H); 6.99 (d, J = 8 Hz, 2H); 6.83(d, J = 9 Hz,2H); 5.12(d, J = 5.5 Hz, 1H); 3.82(s, 3H); 3.75-3.63(m, 1H); 3.52(dd, J= 9.5 Hz, 1H); 2.71-2.57(m, 1H); 2.49-2.33(m, 1H); 1.68-1.50(m, 1H);1.47-1.31)m, 1H)

The 3A, 3B and 3C, diastereomers were further separated according to thefollowing reaction scheme, wherein partial structures are shown:

(The following CD spectra data [θ] are all obtained in CH₃OH.)

3D) [θ]_(227nM)=+2.0×10⁴ cm²/dM; [θ]_(241nM)=−4.6×10⁴ cm²/dM. Elementalanalysis calc for C₂₅H₂₅NO₃−0.25 H₂O: C 76.6; H 6.56 N 3.57. found: C76.66; H 6.49; N 3.64.

3E) [θ]_(227nM)=−1.95×10⁴ cm²/dM; [θ]_(241nM)=+4.45×10⁴ cm²/dM.Elemental analysis calc for C₂₅H₂₅NO₃.0.5 H₂O: C 75.73; H 6.61; N 3.53.found: C 75.66; H 6.41; N 3.60.

3F) [θ]_(226nM)=+1.97×10⁴ cm²/dM; [θ]_(240nM)=−5.22×10⁴ cm²/dM.Elemental analysis calc for C₂₅H₂₅NO₃: C 77.48; H 6.5-1; N 3.62. found:C 77.44; H 6.53; N 3.70.

3G) [θ]_(226nM)=−1.78×10⁴ cm²/dM; [θ]_(241nM)=+4.78×10⁴ cm²/dM (CIMS 388M⁺H).

3H) [θ]_(226nM)=+2.24×10⁴ cm²/dM; [θ]_(241nM)=−5.4×10⁴ cm²/dM. [α]_(D)²⁵=−54.4° (2.5 mg/ml CH₃OH) Elemental analysis calc for C₂₅H₂₅NO₃: C77.48; H 6.51; N 3.62. found: C 77.11; H 6.50; N 3.72.

3I) [θ]_(226nM)=−2.05×10⁴ cm²/dM; [θ]_(241nM)=+5.2×10⁴ cm²/dM. (CIMS 388M⁺H).

Add DEAD (0.11 ml) to a solution of compound 3H (132 mg), PPh₃ (0.18 g)and HCO₂H (39 ml) in THF (5 ml). Stir at room temperatq temperatureovernight, then partition the reaction mixture between Et₂O and H₂O.Wash (brine) and dry (MgSO₄) the organic layer and concentrate todryness. Flash chromatograph the residue using EtOAc:Hex (1:4) to obtainthe formate ester. Dissolve this in CH₃OH and add 4 drops of conc. HCl.After 4 h, concentrate in vacuo and flash chromatograph the residueusing EtOAc:Hex (1:3) to obtain 3J. [θ]_(224nM)=+2.54×10³ cm²/dM;

[θ]_(239nM)=+5.70×10⁴ cm²/dM; [α]_(D) ²⁰=−157.6° (2.5 mg/ml CH₃OH)

Using the procedure described for 3J, treat compound 3I to obtain 3K.[θ]_(222nM)=−3.4×10³ cm²/dM; [α]_(240nM)=−5.6×10⁴ cm²/dM. [α]_(D)²⁰=+167.2° (2.5 mg/ml CH₃OH)

Using the procedure described above for preparing compounds 3A and 3B,treat N-phenyl-4-(4-methoxyphenyl)-2-azetidinone with LICA followed by2-naphthaldehyde to obtain the diastereomers 3L and 3M:

3L

mp 137- 138° C. 3M

mp 150- 151° C.

EXAMPLE 4

Method 1:

Step 1) To a refluxing solution of of 4-methoxyberizylidene anisidine(10.0 g, 41.5 mmol) and tributylamine (20.8 ml, 87 mmol) in toluene (100ml), add 5-bromovaleroyl chloride (8.5 g, 43, mmol) in toluene (20 ml)dropwise over 2 h. Stir the reaction mixture at 80° C. for 12 h, cool toroom temperature, wash 3× with 1 N HCl, 1× with water and dry theorganic layer over MgSO₄. Purify by silica gel chromatography, elutingwith ethyl acetate:hexane (4:1) to obtain 5.1 g of (3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-bromoproyl)-2-azetidinone (relativestereochemistry), mp 70°-73° C., El (M⁺) 404; J=2.3 Hz.

Step 2) To a solution of the product of step 1 (5.1 g, 12.6 mmol) in(CH₃)₂SO (20 ml), add (CH₃)₃N(O) (2.39 g, 31.9 mmol). Heat the mixtureat 60° C. for 3 h, cool to room temperature, dilute with EtOAc, and wash3× with water. Combine the aqueous fractions and extract with EtOAc.Combine the organic fractions and concentrate. Purify the crude productby silica gel chromatography, eluting with EtOAc:hexane (1:1) to obtain1.4 g (3R, 4S)-1,4-bis-(4-methoxyphenyl)-2-oxo-3-azetidine-propanol(relative stereochemistry), an oil; EI (M⁺) 339; J=2.3 Hz.

Step 3) To a solution of the product of step 2 (0.7134 0.734 g, 2.2mmol) in THF (4 ml) at 0° C., add phenylmagnesium bromide (2.4 ml, 2.4mmol, 1.0 M in THF) over 0.25 h. After 1 h at 0° C., add water (5 ml),separate the layers, wash the organic layer 1 × with 1N HCl, dry withMgSO₄ and concentrate to an oil. Purify by silica gel chromatography,eluting with EtOAc:hexane (2:1) to obtain 0.372 g of the title compound(mix of diastereomers) as an oil. CI (M⁺H) 418.

Separation of diastereomers: Apply the diastereomeric mixture from step3 to a Chiralcel OD (Chiral Technologies Corp, Pa.) chromatographycolumn, eluting with hexane:ethanol (9:1) to obtain enantiomericallypure (>98%) diastereomers as follows:

Method 2:

Step 1) To a solution of1,4-(S)-bis(4-methoxyphenyl)-3-(3(R)-phenylpropyl)-2-azetidinone (5.04g, 0.013 mole) in CCl₄ (20 ml) at 80° C., add NBS (2.76 g, 0.0155 mole)and benzoyl peroxide (0.24 g, 1.0 mmole) in three equal portions over 1h. Follow the reaction by TLC (4:1 hexane:EtOAc). Cool the reaction to22° C., add NaHSO₄, separate the layers and wash the organic layer 3×with water. Concentrate the organic layer to obtain the crude product.

CI (M⁺H) 480; ¹H in CDCl₃ δ PhCH(OH)=5.05 ppm.

Step 2) Dissolve the crude product of Step 1 in CH₂Cl₂ (30 ml) and add40% n-BuNOC(O)CF₃ in water (30 ml). Reflux the biphasic reaction for 24h, cool, separate the layers and wash the organic layer 6× with water.Concentrate the organic layer to dryness and immediately redissolve theresidue in ethanol saturated with NH₃ (10 ml). After 1 h, concentratethe reaction mixture and partially purify by silica gel chromatography.Further purify by HPLC to obtain a 1:1 mixture of compounds 4A and 4B.The mixture can be further purified on a Chiracel OD column to obtain 4Aand 4B separately as characterized above.

Using the procedure described in Example 4, Method 2, with4(S)-(4-acetoxyphenyl)-3(R)-(3-phenylpropyl)-1-(4-methoxy-phenyl)-2-azetidinoneas the starting material, prepare the following compounds:

EXAMPLE 5

To a solution of the product of step 2 of Example 4 (0.230 g, 0.68 mmol)in THF (2 ml), add the reagent derived from treatment of4-methoxymethylphenyl bromide (0.159 g, 0.736 mmol) in THF (4 ml) at−78° C. with sec-butyllithium (0.6 ml, 0.78 mol, 1.3M in hexanes),followed by CeCl₃ (0.186 g, 0.75 mmol). After 4 h, extract the productand purify by chromatography in a manner similar to that described instep 3 of Example 4 to obtain 0.05 g of the title compound (mix ofdiastereomers) as an oil. CI (M⁺H) 478.

EXAMPLE 6

Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol)in CH₂Cl₂ (20 ml), add 4-dimethylaminopyridine (2.5 g, 0.02 mol) andtriethylamine (84.7 ml, 0.61 mol) and cool the reaction to 0° C. Addmethyl-4-(chloroformyl)butyrate (50 9 g, 0.3 mol) as a solution inCH₂Cl₂ (375 ml) dropwise over 1 h, and allow the reaction to warm to 22°C. After 17 h, add water and H₂SO₄ (2N, 100 ml), separate the layers,and wash the organic layer sequentially with NaOH (10%). NaCI (sat'd)and water. Dry the organic layer over MgSO₄ and concentrate to obtain asemicrystalline product.

Step 2): To a solution of TiCl₄ (18.2 ml, 0.165 mol) in CH₂ Cl₂ (600 ml)at 0° C., add titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min,add the product of Step 1 (49.0 9, 0.17 mol) as a solution in CH₂ Cl₂(100 ml). After 5 min., add diisopropylethylamine (DIPEA) (65.2 ml, 0.37mol) and stir at 0° C. for 1 h, cool the reaction mixture to −20° C.,and add 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) as asolid. Stir the reaction vigorously for 4 h at −20° C., add acetic acidas a solution in CH₂Cl₂ dropwise over 15 min, allow the reaction towarnr warm to 0° C., and add H₂ SO₄ (2N). Stir the reaction anadditional 1 h, separate the layers, wash with water, separate and drythe organic layer. Crystallize the crude product from ethanol/water toobtain the pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) intoluene (100 ml) at 50° C., add N,O-bis(trimethylsilyl)acetamide (BSA)(7.50 ml, 30.3 mmol). After 0.5 h, add solid TBAF (0.39 g, 1.5 mmol) andstir the reaction at 50° C. for an additional 3 h. Cool the reactionmixture to 22° C., add CH₃OH (10 ml), wash the reaction mixture with HCl(1N), NaHCO₃ (1N) and NaCI (sat'd), and dry the organic layer overMgSO₄.

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) andCH₃OH (3 ml), add water (1 ml) and LiOH.H₂O (102 mg, 2.4 mmole). Stirthe reaction at 22° C. for 1 h and add additional LiOH.H₂O (54 mg, 1.3mmole). After a total of 2 h, add HCl (1N) and EtOAc, separate thelayers, dry the organic layer and concentrate in vacuo. To a solution ofresultant product (0.91 g, 2.2 mmol) in CH₂Cl₂ at 22° C., add ClCOCOCl(0.29 ml, 3.3 mmol) and stir for 16 h. Remove the solvent in vacuo.

Step 5): To an efficiently stirred suspension of 4-fluorophenylzincchloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide 5 (1Min THF, 4.4 ml, 4.4 mmol) and ZnCl₂ (0.6 g, 4.4 mmol) at 4° C., addtetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) and theproduct of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 ml). Stirthe reaction for 1 h at 0° C. and then for 0.5 h at 22° C. Add HCl (1N,5 ml) and extract with EtOAc. Concentrate the organic layer to an oiland purify by silica gel chromatography to obtain1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone:

HRMS calc'd for C₂₄H₁₉F₂NO₃=408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 ml), add(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole(120 mg, 0.43 mmol) and cool the mixture to −20° C. After 5 min, addborohydride-dimethylsulfide complex (2M in THF: 0.85 ml, 1.7 mmol)dropwise over 0.5 h. After a total of 1.5 h, add CH₃OH followed by HCl(1 N) and extract the reaction mixture with EtOAc to obtain1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone(compound 6A-1) as an oil. ¹H in CDCl₃ δ H3=4.68, J=2.3 Hz. CI (M⁺H)500.

Use of(S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone(compound 6B-1). ¹H in CDCl₃ δ H3=4.69, J=2.3 Hz. CI (M⁺H) 500.

To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), add10% Pd/C (0.03 g) and stir the reaction under a pressure (60 psi) of H₂gas for 16 h. Filter the reaction mixture and concentrate the solvent toobtain compound 6A. Mp 164°-166° C.; CI (M⁺H) 410.

[α]_(D) ²⁵=−28.1° (c 3, CH₃OH). Elemental analysis calc'd forC₂₄H₂₁F₂NO₃; C 70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.

Similarly treat compound 6B-1 to obtain compound 6B. Mp 129.5°-132.5°C.; CI (M⁺H) 410. Elemental analysis calc'd for C₂₄H₂₁F₂NO₃: C 70.41; H5.17; N 3.42; found C 70.30; H 5.14; N 3.52.

Step 6′) (Alternative): To a solution of the product of Step 5 (0.14 g,0.3 mmol) in ethanol (2 ml), add 10% Pd/C (0.03 g) and stir the reactionunder a pressure (60 psi) of H₂ gas for 16 h. Filter the reactionmixture and concentrate the solvent to afford a 1:1 mixture of compounds6A and 6B.

Using appropriate starting materials and following the procedure ofsteps 1-6, prepare the following compounds:

EXAMPLE 7

To a solution of 7a (1.0 g, 2.1 mmol) in dioxane (10 ml), add SeO₂ (1.33g, 11.98 mmol) and water (25 ml, 14 mmol), ( 0.25 ml, 14 mmol), and heatthe reaction to 100° C. After 1 h, cool the reaction to room temperatureand isolate by extraction the crude product as a diastereomeric mixture(1:2) of alcohols 7b-A and 7b-B. Purify by HPLC on a Dynamax silicacolumn to separate diastereomers 7b-A and 7b-B.

Diastereomer 7b-A (R): oil; J₃₄=2.3 Hz, δ C H(OH)=4.86 (t); HRMSC₃₂H₂₉NO₄ calc.: 491.2097; found: 491.2074.

Diastereomer 7b-E (S): oil; J₃₄=2.3 Hz, δ C H(OH)=5.06 (t); HRMSC₃₂H₂₉NO₄ calc.: 491.2097; found: 491.2117.

Step 2): To a solution of diastereomer A from step 1 (58 mg, 0.12 mmol)in EtOAc (2 ml), add 10% Pd on carbon (20 mg) and stir at 22° C. underH₂ gas (14 psi) for 12 h. Filter and concentrate to obtain the titlecompound as a semisolid, m.p. 90°-92° C. J₃₄=2.3 Hz, δ CH(OH)=4.1 (m);HRMS C₂₅H₂₅NO₄ calc: 403.1783; found: 403.1792.

EXAMPLE 8

To a solution of the product of Example 4A (90 mg, 0.2 mmol) in CH₂Cl₂,add acetyl chloride (80 mg, 1.0 mmol) and pyridine (8 mg, 0.1 mmol) andstir at room temperature for 1 h. Add water, separate the layers andisolate the corresponding acetoxy compound, 8A. In a similar manner,treat the products of Examples 4B, 6B and 6A to obtain the followingcompounds 8B, 8° C. and 8D, respectively:

8A:1,4(S)-bis(4-methoxyphenyl)-3(R)-(3(R)-acetoxy-3-phenylpropyl)-2-azetidinone.CI (M⁺H) 460; HRMS C₂₈H₂₉NO₅ calc.: 459.2044; found: 459.2045.

8B:1,4(S)-bis(4-methoxyphenyl)-3(R)-(3(S)-acetoxy-3-phenylpropyl)-2-azetidinone.CI (M⁺H) 460; HRMS C₂₈H₂₉NO₅ calc.: 459.2044; found 459.2048.

8C: 4(S)-(4-acetyloxyphenyl)-3(R)-(3(R)-acetyloxiy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone. FAB M:S493.4; HRMS C₂₈H₂₅F₂NO₅ calc.: 493.1695; found: 493.1701.

8D:4(S)-(4-acetyloxyphenyl)-3(R)-(3(S)-acetyloxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone.FAB MS 493.4; HRMS C₂₈H₂₅F₂NO₅ calc.: 493.1695; found: 493.1694.

Using appropriate starting materials in the procedure of Example 6,prepare 1-(4-chlorophenyl)-3(R)-(hydroxy-3.-(4-chlorophenylpropyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone. Using theprocedure of Example 8, prepare the following diacetates 8E and 8F:

EXAMPLE 9

Step 1:

Add pyridinium chlorochromate (2.4 g, 11 mmoles) and CH₃CO₂Na (approx.20 mg) to a solution of1-phenyl-3-(3-phenyl-1-hydroxypropyl)-4-(4-methoxyphenyl)-2-azetidinone(2.35 g, 6.1 mmoles) in CH₂Cl₂. Stir at room temperature for 18 h, thenadd silica gel (40 g) and concentrate to dryness. Flash chromatographthe residue using EtOAc:Hex (1:4) to obtain an oil. (1.98 g, yield=85%).¹H NMR 2.85-2.95 (m, 3H), 3.15 (m, 1H), 3.80 (s, 3H), 4.10 (d, 1H, J2.6), 5.42 (1H, d, 6.85 (dd, 2H, J 2.8), 7.05 (m, 1H), 7.2-7.35 (m,11H).

Step 2:

To a solution of the product of Step 1 (1.78 g, 4.62 mmoles) in THF at−10° C., add NaH (115 mg, 4.8 mmoles). After 15 min, add NBS (865 mg,4.85 mmoles) and stir for 20 min., then add 1N HCl and partition betweenEtOAc and brine. Separate the organic layer, dry (MgSO₄) and concentrateto give an oil. Flash chromatograph the oil using EtOAc:Hex (1:10) tocollect first 9a as a foamy solid (830 mg, y=39%, FAB MS 466/464, M+H),and then 9b as a colorless solid (1.1 g, y=51%, FAB MS 466/464, M+H).

Step 3a:

Add Mg(OCOCF₃)₂.CF₃CO₂H (7.3 ml of 1M solution is Et₂O.) to a solutionof 9a (0.68 g, 1.46 mmoles) in THF (5 ml) at −50° C. Stir the reaction 5min., then add t-Bu—NH₂-BH₃ (254 mg, 2.92 mmole). After 15 min., allowthe reaction to warm to 0° C. over 20 min., add 1N HCl and concentratein vacuo. Partition the residue between EtOAc and brine. Concentrate theorganic layers and dissolve the resultant oil in CH₂Cl₂:CH₃OH (1:1) andadd ethanolamine (approx 2 mmoles). After 15 min., concentrate thereaction mixture and partition the residue with EtOAc:1N HCl. Wash(brine) and dry (MgSO₄) the organic layer to obtain an oil. Purify thisoil by flash chromatography using EtOAc:Hex (1:4) to obtain compound9a-1, a colorless solid, as a 4:1 mix of diastereomers. 0.52 g, y=76%,SIMS 468/466 (M+H).

Step 3b:

Using compound 9b as the starting material, use a procedure similar toStep 3a with CH₂Cl₂ as solvent for the preparation of 9b-1 in 80% yieldas a 13:1 mixture of diastereomers (SIMS 468/466 M+H).

Step 4a:

Add a solution of 9a-1 (0.27 g, 0.58 mmoles) and AIBN (18 mg, 0.12mmole) in toluene (40 ml) dropwise over 40 min. to a solution of(TMS)₃SiH (1.0 ml) in toluene at 80° C. for 1.5 h. Cool and concentratethe reaction mixture, dissolve the residue in CH₃CN and wash 3× withhexane. Concentrate the CH₃CN layer to give the title compound as aracemic mixture (0.25 g). Purify this oil by HPLC using a Chiralcel ODcolumn to obtain 3H (major) and 3J (minor).

Step 4b:

Use the procedure of Step 4a, starting with compound 9b-1 to obtain anoil. Purify this by flash chromatography using EtOAc:Hex (1:3) tocollect the racemic title compound (y=70%). Purify this oil by HPLCusing a Chiralcel OD column to obtain 3J (major) and 3H (minor).

EXAMPLE 10

Step 1:

Follow the procedure of Example 3, using1-(4-fluorophenyl-4-(4-t-butyldimethylsilyloxyphenyl)-2-azetidinone toobtain 1-(4-fluorophenyl-3-(3-phenyl-1-hydroxypropyl)4-(4-t-butyldimethylsilyl-oxyphenyl)-2-azetidinone.

Step 2:

Treat a solution of the cis-azetidinone of Step 1 (0.25 g) in CH3CN CH₃CN (21 ml) with 48% aqueous HF (2.5 ml). After 18 h, dilute the reactionmixture with cold H₂O and extract with Et₂O. Wash (2× H₂O, dilute NaHCO₃and brine), dry (MgSO₄) and concentrate the Et₂O layer. Crystallize theresidue from EtOAc:hexane (1:2) to obtain the title compound ascolorless needles (123 mg, y=64%), mp 168°-171° C. Elemental analysiscalc for C₂₄H₂₂O₃FN: C 73.64; H 5.66; N 3.58. found C 73.32; H 5.65; N3.68.

The following formulations exemplify some of the dosage of thisinvention. In each the term “active compound” designates a compound offormula I.

EXAMPLE A

Tablets No. Ingredient mg/tablet mg/tablet 1 Active Compound 100 500 2Lactose USP 122 113 3 Corn Starch, Food Grade, as a 10%  30  40 paste inPurified Water 4 Corn Starch, Food Grade  45  40 5 Magnesium Stearate  3 7 Total 300 700

Method of Manufacture

Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate themixture with Item No. 3. Mill the damp granules through a coarse screen(e.g., ¼′, 0.63 cm) if necessary. Dry the cl damp granules. Screen thedried granules if necessary and mix with Item No. 4 and mix for 10-15minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture toappropriate size and weight on a suitable tablet machine.

EXAMPLE B

Capsules No. Ingredient mg/tablet mg/tablet 1 Active Compound 100 500 2Lactose USP 106 123 3 Corn Starch, Food Grade  40  70 4 MagnesiumStearate NF  4  7 Total 250 700

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture suitable two-piecehard gelatin capsules on a suitable encapsulating machine.

Representative formulations comprising a cholesterol biosynthesisinhibitor are well known in the art. It is contemplated that where thetwo active ingredients are administered as a single composition, thedosage forms disclosed above for substituted azetidinone compounds mayreadily be modified using the knowledge of one skilled in the art.

Using the test procedures described above, the following in vivo datawere obtained for the exemplified compounds. Data is reported as percentchange (i.e., percent reduction in cholesterol esters) versus control,therefore, negative numbers indicate a positive lipid-lowering effect.

% Reduction Serum Cholest. Dose Ex. # Cholest. Esters mg/kg 1A −23 0 501B −15 −39 50 1C 14 0 50 2 0 0 50 3A −31 −69 50 3C −60 −92 50 3D −17 −6110 3E 0 0 10 3F −29 −77 10 3G −16 −38 10 3H −41 −86 10 3I 0 −22 10 3J 00 3 3K 0 0 10 3L −15 −21 10 3M 0 −22 10 4A 0 −54 5 4B −37 −89 8 4C −12.50 3 4D 9 0 7 4E 0 −46 3 4F −29 −95 3 5 0 −64 10 6A −59 −95 1 6A-1 −43−93 1 6B −40 −92 3 6C 0 −48 3 6D −46 −95 10 8A 0 −44 3 8B −50 −95 3 8C−14 −37 1 8D −49 −98 1 8E −22 −66 3 8F −43 −94 1 10 −26 −77 3

We claim:
 1. A compound represented by the formula

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ and Ar² are independently selected from the group consisting of aryl and R⁴-substituted aryl; Ar³ is aryl or R⁵-substituted aryl; X, Y and Z are independently selected from the group consisting of —CH₂—, —CH(lower alkyl)- and —C(dilower alkyl)-; R and R² are independently selected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷; R¹ and R³ are independently selected from the group consisting of hydrogen, lower alkyl and aryl; q is 0 or 1; r is 0 or 1; m, n and p are independently 0, 1, 2, 3 or 4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5; R⁴ is 1-5 substituents independently selected from consisting of lower alkyl, —OR⁶, —O(CO)R⁶, —O(CO) OR⁹, —O(CH₂)₁₋₅OR⁶, —(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, -COR⁶, -SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶, —CH═CH—COOR⁶, —CF₃, —CN, —NO₂ and halogen; R⁵ is 1-5 substituents independently selected from the group consisting of —OR⁶, —O(CO)R⁶, —O(CO) OR⁹, —O(CH₂)₁₋₅OR⁶, —(CO)NR⁶R⁷, —NR⁶R⁷, —NR⁶(CO)R⁷, —NR⁶(CO)OR⁹, —NR⁶(CO)NR⁷R⁸, —NR⁶SO₂R⁹, —COOR⁶, —CONR⁶R⁷, —COR⁶, —SO₂NR⁶R⁷, S(O)₀₋₂R⁹, —O(CH₂)₁₋₁₀—COOR⁶, —O(CH₂)₁₋₁₀CONR⁶R⁷, -(lower alkylene)COOR⁶ and —CH═CH—COOR⁶; R⁶, R⁷ and R⁸ are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R⁹ is lower alkyl, aryl or aryl-substituted lower alkyl.
 2. A compound of claim 1 wherein Ar¹ is phenyl or R⁴-substituted phenyl, Ar² is phenyl or R⁴-substituted phenyl and Ar³ is R⁵-substituted phenyl.
 3. A compound of claim 2 wherein Ar¹ is R⁴-substituted phenyl wherein R⁴ is halogen; Ar² is R⁴-substituted phenyl wherein R⁴ is halogen or —OR⁶, wherein R⁶ is lower alkyl or hydrogen; and Ar³ R⁵-substituted phenyl, wherein R⁵ is —OR⁶, wherein R6 is lower alkyl or hydrogen.
 4. A compound of claim 1 wherein X, Y, and Z are each —CH₂—; R¹ and R³ are each hydrogen; R and R² are each —OR⁶, wherein R⁶ is hydrogen; and the sum of m, n, p, q and r is 2, 3 or
 4. 5. A compound of claim 1 wherein m, n and r are each zero, q is 1 and p is
 2. 6. A compound of claim 1 wherein p, q and n are each zero, r is 1 and m is 2 or
 3. 7. A compound selected from the group consisting of rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(R)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; rel 3(R)-(2(R)-hydroxy-2-phenylethyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 3(S)-(1(S)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 3(S)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 3(R)-(1(R)-hydroxy-3-phenylpropyl)-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; rel-3(R)-[(S)-hydroxy-(2-naphthalenyl)methyl]-4(S)-(4-methoxyphenyl)-1-phenyl)-1-phenyl-2-azetidinone; rel-3(R)-[(R)-hydroxy-(2-naphthalenyl)methyl]-4(S)-(4-methoxyphenyl)-1-phenyl-2-azetidinone; 3(R)-(3(R)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl-2-azetidinone; 3(R)-(3(S)-hydroxy-3-phenylpropyl)-1,4(S)-bis-(4-methoxyphenyl-2-azetidinone; 4(S)-(4-hydroxyphenyl)-3(R)-(3(R)-hydroxy-3-phenylpropyl-1-(4-methoxyphenyl)-2-azetidinone; 4(S)-(4-hydroxyphenyl)-3(R)-(3(S)-hydroxy-3-phenylpropyl-1-(4-methoxyphenyl)-2-azetidinone; rel 3(R)-[3(RS)-hydroxy-3-[4-methoxymethoxy)-phenyl]propyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone; 1-(4-fluorophenyl)-3(R)-[3(R)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone; 4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(R)-hydroxy-3-phenylpropyl)-1-(4-methoxyphenyl)-2-azetidinone; 4(S)-[4-(acetyloxy)phenyl]-3(R)-(3(S)-hydroxy-3-phenylpropyl)-1-(4-methoxyphenyl)-2-azetidinone; 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone; 3(R)-[3(R)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 3(R)-[3(S)-acetyloxy)-3-phenylpropyl]-1,4(S)-bis-(4-methoxyphenyl)-2-azetidinone; 3(R)-[3(R)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl]-1-(4-fluorophenyl)-2-azetidinone; 3(R)-[3(S)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl]-1-(4-fluorophenyl)-2-azetidinone; 3(R)-[3(R)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl]-1-(4-chlorophenyl)-2-azetidinone; 3(R)-[3(S)-(acetyloxy)-3-(4-chlorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl]-1-(4-chlorophenyl)-2-azetidinone; and rel 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(1R)-(1(R)-hydroxy-3-phenylpropyl)-2-azetidinone.
 8. A pharmaceutical composition for the treatment or prevention of athersclerosis , atherosclerosis or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.
 9. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need of such treatment an effective amount of a compound of claim
 1. 10. A compound comprising 1-( 4 -fluorophenyl)- 3 (R)-[3 (S)-( 4 -fluorophenyl)- 3 -hydroxypropyl)]- 4 (S)- 4 -(hydroxyphenyl)- 2 -azetidinone or a pharmaceutically acceptable salt thereof.
 11. A compound represented by the formula:


12. A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising an effective amount of a compound according to claims 10 or 11 in a pharmaceutically acceptable carrier.
 13. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 10 or
 11. 